Unlike many other cell types, neurons cannot be replaced in the adult brain. Thus, neuron loss in the adult brain has crippling and generally irreversible consequences whether it is caused by age, disease, trauma, or combinations thereof.
The cause of neuron loss during aging is unknown. Yet, there is increasing evidence suggesting that almost everyone who lives long enough may succumb to age-related diseases, such as Alzheimer's disease (AD), Parkinson's disease (PD), and stroke, which are generally associated with neuron loss in different regions of the brain. The incidence of many neurodegenerative diseases increases rapidly with aging. For example, the percent of the individuals below age sixty-five who have Alzheimer's disease is less than five percent, but this incidence increases almost exponentially over age sixty-five, and as many as forty-seven percent of individuals over eighty-five years of age may have some form of AD. Katzman, R. and Saitoh, T. (1991) FASEB J. 5:278-286; Evans, D. A. et al. (1989) JAMA 262:2551-2556. Moreover, the brains of essentially all individuals studied over age eighty contain at least some age- and/or disease-related neuron loss. Matsuyama, H. et al. (1966) Proceedings of the Fifth International Congress of Neuropathology (Excerpta Medica International Congress Series No. 100, eds. Luthy, F. et al.) 979-980. Thus, aging itself is the major risk factor for several types of neurodegenerative diseases, indicating that aging increases susceptibility to neuron loss. In fact, there is much evidence that aging, even in the absence of disease, is also associated with neuron loss and memory impairment. Crook, T. et al. (1986) Devel. Neuropsych. 2(4):261-276.
Although the cause of neuron loss in aging and neurodegenerative diseases remains unknown, one model has been termed the "altered calcium homeostasis hypothesis". This hypothesis is that dysregulated or elevated intracellular calcium levels is a "final common pathway" for many neurodegenerative conditions and diseases that eventually leads to neuron death. It is based to a large extent on evidence of calcium dysregulation in age-related deterioration of the nervous system in animal models of aging. Khachaturian, Z. S. (1984) Handbook of Studies on Psychiatry and Old Age (eds. Kay, D. and Buarrows, G. D., Elsevier, Amsterdam) 7-30; Khachaturian, Z. S. (1989) Aging 1:17-34; Gibson, G. E. and Peterson, C. (1987) Neurobiol. Aging 8:329-344; Landfield, P. W. (1987) Neurobiol Aging 8:346-347. It has also been shown that dysregulated or elevated intracellular calcium can lead to overactivation of enzymes, such as calcium dependent proteases and endonucleases, that can be toxic to cells. Siesjo, B. K. (1981) J. Cereb. Blood Flow Metab. 1:155-185; Choi, D. W. (1987) J Neurosci. 7:369-379.
While aging appears to affect calcium regulation in the brain, investigations of peripheral calcium regulation in relation to conditions and diseases, for example, AD, a disease marked by extensive neuron loss, notably in the hippocampus, generally have been inconsistent. A number of studies have found that neither parathyroid hormone, vitamin D, nor serum calcium differ systematically between diseased patients and age-matched controls (Shore, D. et al. (1980) J. Gerontol. 35:656-662; Singh, S. (1988) Age Ageing 17:21-28; Ferrier, I. N. et al. (1990) Age Ageing 19:368-375), while a few have found that some aspects of calcium regulation are altered in diseased patients. Martyn, C. N. et al. (1989) Gerontology 35:153-157; Ferrier, I. N. et al. (1990) Age Ageing 19:368-375; Ogihara, T. et al. (1990) Gerontology 36 (Supp. 1): 25-30.
There have also been studies attempting to find alterations in peripheral calcium regulating hormones with normal aging. Some of these studies found changes in calcium regulation and calcium regulating hormones such as vitamin D. Orwoll, E. S. and Meier, D. E. (1986) J. Clin. Endocrinol. Metab. 63:1262-1269. However, all of these studies of peripheral calcium regulation in aging and even in AD have been correlational, and none has shown any causal link between peripheral calcium regulating hormones and neuron loss. In fact, none of these studies has even suggested that vitamin D might affect brain calcium regulation or brain neuron loss. This is probably due to the generally held belief that peripheral hormones do not modulate brain calcium regulation. Thus, the concept of calcium regulation by vitamin D has not been related to the altered calcium homeostasis hypothesis of brain aging.
Thus, the genetic or environmental cause(s) of brain aging or death of brain neurons, remain largely undefined. Clearly, whatever the cause, it is the progressive and cumulative effect of neuron death over a long period of time that results in perceptible physiological changes. Progression of cognitive symptoms due to AD have been found in longitudinal studies to be detectable at intervals of no less than one month to one year. Morris, J. C. et al. (1989) Neurology 39:1159-1165 (Tables 3 and 6). Hippocampal neuron loss due to normal brain aging is even more gradual. Ball, M. J. (1977) Acta Neuropathol. (Berl.) 37:111-118; Coleman, P. D. and Flood, D. G. (1987) Neurobiol. of Aging 8:521-545. Thus, testing over a period of not less than one month, up to a period of perhaps several years, is necessary to show evidence of reduced neuron loss upon treatment of a subject with a drug that is purported to be useful in the treatment of age- or disease-related neurodegeneration.
U.S. Pat. No. 4,897,388, issued in 1990 on an application filed in December, 1988 discloses a method of treating patients with Alzheimer's disease through the administration of a safe and effective amount of a biologically active vitamin D.sub.3 or D.sub.2 material. One patient suffering from Alzheimer's disease was treated with calcitriol for a period of seven days. The patient's condition, the symptoms of which were not defined, reportedly showed improvement. However, the period over which testing was performed is completely insufficient, for the reasons stated above, to show evidence of reduced neuron loss. Additionally, the sample consisting of a single patient is not large enough from which to determine any conclusions, even assuming that the improvement was objectively determined. Finally, there is no explanation of the type of improvement observed but it is likely to be only the relief of AD symptoms caused by peripheral effects of the vitamin D material.
Loss of neurons from the brain is thought to be a general characteristic of aging, affecting virtually all of the population. Progressive neuron loss leads, in many circumstances, to the onset and progression of debilitating neurodegenerative diseases, thus presenting a major healthcare burden for the population. For example, almost $90 billion was spent in 1991 alone on the treatment of patients with Alzheimer's disease. (Alzheimer's Association, Chicago, Ill.) This is just one example of many diseases that may result from neuron loss. Any remedy which could treat, or in the optimal case, prevent, occurrence of age-related neurological diseases by preventing neuron loss would be an immense healthcare savings as well as a great improvement in the health outlook for large number of the population. It is therefore imperative to develop therapies which can halt or slow the progression of neuron loss. Such therapies would optimally work over a long period of time as neuron loss occurs over a long period of time, and be safe in such time frames with efficacious dosages. For the foregoing reasons, there remains a critical need for a method of long term treatment that will prevent or retard neuron loss in a subject.